Shining a light on autophagy in neurodegenerative diseases.

Small-molecule modulators of autophagy have been widely investigated as potential therapies for neurodegenerative diseases. In a recent issue of JBC, Safren et al. described a novel assay that uses a photoconvertible fusion protein to identify compounds that alter autophagic flux. Autophagy inducers identified using this assay were found to either alleviate or exacerbate neurotoxicity in different cellular models of amyotrophic lateral sclerosis, challenging the notion that autophagy stimulation can be used as a one-size-fits-all therapy for neurodegenerative disease.

Plastic Surgery Practice during COVID Times.

Introduction COVID-19 has affected plastic surgeons like never before. We conducted an all-India survey to find how the practice was affected among public/private sector, reconstructive/aesthetic practice, and consultants/residents. We have proposed some solutions to the identified problems, which are supported by previous literature. Methods A survey framed in Google forms was circulated through WhatsApp and emails in August 2020. Closed and semiopen questions regarding changes in personal and professional lives, coping strategies adopted, and open questions for suggestions in improving practice, academics and measures to tackle the pandemic were included. Responses were collected in an Excel sheet and analysis done using SPSS software. Results A total of 220 consented responses were obtained. Public hospital practitioners had to bear the COVID-related administrative as well as executive works, especially residents, which led to anxiety, family concern, burnout, and concern about the loss of skills and academics. Patient interaction was also reduced. Aesthetic surgeons bore more financial loss. Conclusions Plastic surgeons in India faced decrease in caseload, financial loss, COVID-related duties, workload for residents, reduced academics, family and mental health problems, difficulty with personal protection equipment (PPE) during surgeries, and queries from patients. These can be solved by doing cases within the limits of protocols and safety, pooling public and private sector for COVID duties, rotating residents' groups to reduce workload, using telemedicine for academics and patient consultations, and providing social support groups to surgeons.

Its Not about the Destination, Its about the Journey-Plotting 50 Years of Changing Clinical Trends in Plastic Surgery in a Public Sector Teaching Hospital.

Background The year 2019 marked the 50th anniversary of plastic surgery department of our institution. We present an audit to plot the changing clinical trends in our work in the past five decades. Methods A single-center retrospective cohort study based on the department demographics was performed and compared across the decades from 1969 to 2019. Results In 1969, the relative proportion of reconstructive versus cosmetic surgery procedures was 94.32% versus 5.68%; in 2019 this was 76.25% and 23.75%, respectively. An increase of 22 times increase in outpatient registrations, 13.1 times in total surgeries, 642 times in trauma reconstruction, 290 times for hand surgeries, and 323 times for skin tumor surgeries was noted. Male patients (64.9%) increased every decade more than females (35.1%), mostly for trauma surgery and gynecomastia correction. Proportion of pediatric cleft patients have markedly decreased. Spectrum of surgical procedures have widened. Top five reconstructive surgeries in 2019 were limb trauma reconstruction, skin tumor surgeries, hand surgeries, arterio-venous fistula (AV) creation, and oculoplasty. The most common surgery performed was cleft lip surgery in 1969 and hand surgery in 2019. The top five cosmetic surgeries performed in 2019 were scar revisions, nevus excision, liposuction and gynecomastia correction, rhinoplasty, and otoplasty. Conclusions Data collection and archiving and periodic audits help us study changing trends in our field compared with the global trends. Knowing societal demands will help to improve the resident training in teaching hospitals.

Elemental Mercury Poisoning by Self-Injection - A Report of Two Cases.

Injection of mercury into the upper limb is a rare method of self-harm. We report two patients with varied clinical presentations - a 19-year-old male student who injected himself with mercury extracted from a sphygmomanometer bulb and reported to our emergency department 24 hours after the event and a 34-year-old industry worker who presented 2 years after injecting himself with elemental mercury. The management of mercury poisoning is described along with a brief review of literature. Mercury is a toxic element and adequate safety precautions must be taken by the surgical team in the management of such patients. Level of Evidence: Level V (Therapeutic).

VAMP2 regulates phase separation of α-synuclein.

α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson's disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology.

Cyanoacrylate vs. sutures in clean and clean-contaminated surgical wounds - a randomised control study.

Objectives: Various techniques of closure of surgical incisions have been described ranging from various suture materials, staples and tapes to adhesive compounds. Cyanoacrylate is an adhesive compound available for surgical incision closure. Although sutures have been the preferred universal choice for surgical incision closure, glue is gaining popularity in specific places like pediatric injuries, facial injuries, laparoscopic incision closure, etc. This study aimed to compare the results between the application of cyanoacrylate and conventional suturing. Methods: In this randomized control study, patients were divided into two groups of 100 each. The surgical incisions were closed using cyanoacrylate glue in Group A patients and polyamide (EthilonTM 2-0) in Group B patients. Post-operative pain was assessed using Visual Analogue Scale on the first, third, and seventh day. The wounds were evaluated for complications on post-op days 1, 3, 7, and 30 using the ASEPSIS score. Cosmetic outcome was assessed at the end of first month using the Modified Hollander Cosmesis Scale. Results: Post-operative pain was significantly less in the glue group on days 1, 3, and 7. Wound infection with dehiscence occurred in 4 cases (4 %) in Group A and one patient (1 %) in Group B, which was statistically insignificant. There was no significant difference in cosmetic outcomes in either Group. Conclusions: Cyanoacrylate is a good alternative to sutures in skin closure of clean and clean-contaminated surgical wounds.

Neuronal exosomal miRNAs modulate mitochondrial functions and cell death in bystander neuronal cells under Parkinson's disease stress conditions.

Parkinson's Disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra part of the brain. Pathology spread to numerous brain regions and cell types suggests that intercellular communication is essential to PD progression. Exosomes mediate intercellular communication between neurons, glia, and other cell types throughout PD-relevant brain regions. However, the mechanism remains unclear, and its implication in PD pathology, is not well understood. In the current study, we explored the role of exosomes in modulating the response to PD-relevant toxicants. In cellular models of PD, neuronal cell-derived exosomes are readily internalized by recipient neuronal cells as intact vesicles. Internalized exosomes in bystander neuronal cells localize to mitochondria and dysregulate mitochondrial functions, leading to cell death under PD stress conditions. NGS analysis of exosomes released by neuronal cells subjected to PD stress conditions showed that levels of specific miRNAs were altered in exosomes under PD stress conditions. Bioinformatic analysis of the miRNA targets revealed enriched pathways related to neuronal processes and morphogenesis, apoptosis and ageing. Levels of two miRNAs, hsa-miR-30a-5p and hsa-miR-181c-5p, were downregulated in exosomes under PD stress conditions. Expression of the identified miRNAs in neuronal cells led to their enrichment in exosomes, and exosome uptake in neuronal cells ameliorated mitochondrial dysfunction induced by PD stress conditions and rescued cell death. In conclusion, loss of enrichment of specific miRNAs, including miR-30a-5p and miR-181c-5p, under PD stress conditions causes mitochondrial dysfunction and neuronal death, and hence may lead to progression of PD.

Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases.

A hallmark of aging and neurodegenerative diseases is a disruption of proteome homeostasis ("proteostasis") that is caused to a considerable extent by a decrease in the efficiency of protein degradation systems. The ubiquitin proteasome system (UPS) is the major cellular pathway involved in the clearance of small, short-lived proteins, including amyloidogenic proteins that form aggregates in neurodegenerative diseases. Age-dependent decreases in proteasome subunit expression coupled with the inhibition of proteasome function by aggregated UPS substrates result in a feedforward loop that accelerates disease progression. Nuclear factor erythroid 2- like 1 (NFE2L1) is a transcription factor primarily responsible for the proteasome inhibitor-induced "bounce-back effect" regulating the expression of proteasome subunits. NFE2L1 is localized to the endoplasmic reticulum (ER), where it is rapidly degraded under basal conditions by the ER-associated degradation (ERAD) pathway. Under conditions leading to proteasome impairment, NFE2L1 is cleaved and transported to the nucleus, where it binds to antioxidant response elements (AREs) in the promoter region of proteasome subunit genes, thereby stimulating their transcription. In this review, we summarize the role of UPS impairment in aging and neurodegenerative disease etiology and consider the potential benefit of enhancing NFE2L1 function as a strategy to upregulate proteasome function and alleviate pathology in neurodegenerative diseases.

Protective Effects of Polyphenol-Rich Extracts against Neurotoxicity Elicited by Paraquat or Rotenone in Cellular Models of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder involving motor symptoms caused by a loss of dopaminergic neurons in the substantia nigra region of the brain. Epidemiological evidence suggests that anthocyanin (ANC) intake is associated with a low risk of PD. Previously, we reported that extracts enriched with ANC and proanthocyanidins (PAC) suppressed dopaminergic neuron death elicited by the PD-related toxin rotenone in a primary midbrain culture model. Here, we characterized botanical extracts enriched with a mixed profile of polyphenols, as well as a set of purified polyphenolic standards, in terms of their ability to mitigate dopaminergic cell death in midbrain cultures exposed to another PD-related toxicant, paraquat (PQ), and we examined underlying neuroprotective mechanisms. Extracts prepared from blueberries, black currants, grape seeds, grape skin, mulberries, and plums, as well as several ANC, were found to rescue dopaminergic neuron loss in PQ-treated cultures. Comparison of a subset of ANC-rich extracts for the ability to mitigate neurotoxicity elicited by PQ versus rotenone revealed that a hibiscus or plum extract was only neuroprotective in cultures exposed to rotenone or PQ, respectively. Several extracts or compounds with the ability to protect against PQ neurotoxicity increased the activity of the antioxidant transcription factor Nrf2 in cultured astrocytes, and PQ-induced dopaminergic cell death was attenuated in Nrf2-expressing midbrain cultures. In other studies, we found that extracts prepared from hibiscus, grape skin, or purple basil (but not plums) rescued defects in O2 consumption in neuronal cells treated with rotenone. Collectively, these findings suggest that extracts enriched with certain combinations of ANC, PAC, stilbenes, and other polyphenols could potentially slow neurodegeneration in the brains of individuals exposed to PQ or rotenone by activating cellular antioxidant mechanisms and/or alleviating mitochondrial dysfunction.

Distribution of antibiotic resistance and virulence factors among the bacteria isolated from diseased Etroplus suratensis.

Considering the emerging concern with the antimicrobial resistance (AMR) evolution, the study has been designed to identify the antibiotic resistance and virulence properties of culturable bacteria isolated from the diseased fish Etroplus suratensis. This has resulted in the purification of 18 morphologically distinct bacterial isolates which were identified by both biochemical and molecular methods. Antibiotic resistance analysis showed the resistance of these isolates to multiple antibiotics and remarkable evolution of AMR. Further screening for virulence factors confirmed five isolates to be positive for haemolytic activity, eight with caseinase, four with DNase, one with gelatinase and three with biofilm-forming properties. In addition to these, the isolates were subjected to PCR-based screening to detect the presence of genes coding for aerolysin and haemolysin. Results showed the presence aerolysin gene in the isolates ESS3.2, ESS3.8, ESI3.3 and ESS3.6, while haemolysin gene was observed to be present in ESG3.1 and ESI3.2. The observed results hence indicate the need for frequent monitoring of these properties among bacterial isolates from diverse environment especially those associated with edible fish.

Alpha-Synuclein Is a Target of Fic-Mediated Adenylylation/AMPylation: Possible Implications for Parkinson's Disease.

During disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called unfolded protein response that functions to maintain endoplasmic reticulum (ER) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification called Fic-mediatedadenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an adenosine monophosphate (AMP) to the ER chaperone, BiP, to alter the cell's unfolded protein response-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE-alpha-synuclein (αSyn), a presynaptic protein involved in Parkinson's disease. Aggregated αSyn has been shown to induce ER stress and elicit neurotoxicity in Parkinson's disease models. We show that HYPE adenylylates αSyn and reduces phenotypes associated with αSyn aggregation invitro, suggesting a possible mechanism by which cells cope with αSyn toxicity.